Modeling Alzheimer's Disease Related Dementias in the Marmoset

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Abstract The long-term goal of this project is to model Alzheimer's Disease related dementias (ADRD) in longer-living mammals. These multi-dimensional mammalian ADRD models, including frontotemporal degeneration (FTD), Lewy body dementia (LBD), vascular contributions to cognitive impairment and dementia (VCID), and mixed etiology dementias, are aimed at informing human ADRD across the disease-relevant stages and serve as tools to interrogate disease mechanisms and identify therapeutic targets. ADRD develops as a result of a complex series of events that take place in the brain over a long period of time—the prodromal phase can last 10-20 years in humans—before dementia is clinically diagnosed. Understanding this EARLY stage will be critically important for developing diagnostic tools (e.g., neuroimaging) and for screening compounds to prevent or modify disease progression in humans. A variety of ADRD mouse models have been developed to advance research into the underlying molecular and cellular mechanisms, to identify therapeutic targets, and to test therapeutic candidates. While existing ADRD mouse models have enabled progress toward each of these objectives, those available to date do not recapitulate the full spectrum and complexity of the molecular, cellular, behavioral and cognitive pathology observed in typical dementias. Several lines of evidence suggest that marmosets have emerged as a non-human primate model for both basic and translational neuroscience to bridge the gap between mice and humans. First, marmosets and humans have very similar complexity in brain structures, cognitive/social behavioral repertoires, metabolisms and immune functions. Second, as compared to other primates, it is highly economical and scalable for understanding brain functions and preclinical tests because they have a short lifespan, small body size, and high reproductive power. Finally, a set of gene editing tools is available to generate various types of genetically modified marmosets. Several lines of evidence led us to elucidate the role of the triggering receptor expressed on myeloid cells 2 (TREM2) pathways in ADRD. First, homozygous TREM2 null mutations have been linked to a recessive early-onset dementia syndrome called Nasu–Hakola disease. Several TREM2 variants are pathologic to FTD and a major risk factor/modifier for AD, Parkinson's disease, and amyotrophic lateral sclerosis (see https://www.alzforum.org/mutations/trem2). TREM2 mutation precipitates changes in vascular changes and blood brain barrier damages and may contribute to VCID. Second, microglia have emerged as a key cell type in the maintenance of central nervous system homeostasis, for which TREM2 mediates multiple critical signaling pathways. Third, aging is a major risk factor for ADRD. Decreased TREM2 expression during aging may accelerate ADRD development. Taken together , TREM2 is poised to influence neuronal and vascular systems associated with the development of multiple forms of ADRD. To elucidate the role of TREM2 in ADRD, different genetically modified marmosets will be generated and characterized.